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??? Review Acta Cardiol Sin 2010;26:139-41 Computational Modeling of Inherited Arrhythmogenic Disorders of the Heart for Targeted Pharmacotherapy: Introducing an Emerging Cardiac Electrophysiology Research Tool Ruey J. Sung,1 Chu-Pin Lo,2 Pi-Yin Hsiao3 and Hui-Chun Tien2 (RyR2). The Markov model of the I Ca,L channel has a conducting mode (ModeV) and a non-conducting mode (ModeCa). ModeV contains four closed states, a single conducting state, an inactivation state into which channels move fast (IVf) following depolarization and another inactivation state into which channels move slowly (IVs). ModeCa represents channels that are inactivated due to Ca2+. Additionally, channels can also move into another non-conducting Modeq as channels are activated in the presence of isoproterenol. Transitions among these states are affected by changes in voltage and Ca2+ concentrations. The ICa,L channel interacts with the Markov model of ryanodine receptor (RyR2) in restricted ttubular subsarcolemal space for Ca2+ distribution. Intracellular Ca2+ cycling processes include Ca2+ uptake and release by SR and a buffering system (e.g., calmodulin, troponin, and calsequestrin). We simulated various clinical scenarios of TS with stepwise increase in the percentage of G406R-mutated Ca v 1.2 channels, which have been shown to suppress voltage-dependent inactivation of the channel, from 0 to 11.5 and 23%, and to 38.5 and 77%, respectively, for heterozygous and homozygous states of TS1 and TS2.5 Progressive prolongation of action potential duration (APD) and QT interval accompanied by amplification of transmural dispersion of repolarization (TDR) (Figure 1), steepening of APD restitution, induction of delayed afterdepolariztions (DADs) and both DAD- and phase3-early-afterdepolariztion-mediated triggered activities correlated well with the extent of G406R Cav1.2 channel mutation. BAS amplified TDR, steepened APD restitution and facilitated the inducibility of DAD-mediated triggered activity. Systematic analysis of intracellular Computational modeling of human diseases is an emerging field of research interests.1-4 The methodology applied is absolutely non-invasive, producing no harm to the patient or animals, and information so obtained is useful for identifying and/or confirming the underlying pathogenetic mechanism. In this communication, we describe how modeling can recapitulate clinical features of inherited arrhythmogenic disorders of the heart. Taking Timothy syndrome (TS), a malignant form of long QT syndrome referred to as LQT8, in which patients seldom survive beyond three years of age, as an example, modeling was intended to define the mechanism by which recurrent ventricular tachyarrhythmias could be provoked by enhanced sympathetic tone (e.g., exertion and/or emotional distress) and to search for potential targeted sites for pharmacotherapy beyond beta-adrenergic blockers which clinically often fail to provide complete protection.5 The study used the latest state-of-the-art Luo-Rudy guinea pig ventricular myocyte model,1-3,6 which is formulated with various ion channels based on the Hodgkin-Huxley theme and is also incorporated with interacting structure-based Markov models (gating mechanisms) of the L-type Ca2+ channel (ICa,L) and ryanodine receptor Received: March 17, 2010 Accepted: May 4, 2010 1 Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; 2Institute of Applied Mathematics, Providence University, Taichung; 3Institute of Life Sciences, National Central University, Taoyuan, Taiwan. Address correspondence and reprint requests to: Dr. Ruey J. Sung, Institute of Life Sciences, National Central University, No. 300, Jhonda Road, Jhongli, Taoyuan, Taiwan. Tel: 886-3-422-7151 ext. 65071; Fax: 886-3-422-8482; E-mail: [email protected] 139 Acta Cardiol Sin 2010;26:139-41 Ruey J. Sung et al. Figure 1. Prolongation of action potentials and the QT interval associated with 23% G406R Cav1.2 mutation. Endo, M, and Epi = simulated endocardial, mid-myocardial and epicardial myocytes respectively. ECG = pseudo ECG obtained from 1-D strand model. WT = wild type. Modified from Figure 2 of Am J Physiol Heart Circ Physiol 2010;298: H33-44 with permission. Figure 2. Facilitation of induction of DAD-mediated triggered activity in the 23% G406R Ca v 1.2 mutant. Under the influence of betaadrenergic stimulation (BAS), electrical pacing for 12 stimuli fails to provoke any arrhythmia in control (the wild type) (not shown) and in contrast, it provokes DAD-mediated triggered activity. The vertical arrow points to the last paced beat and the diagonal arrows identify those currents initiated by transient inward currents (Inaca and Insca) in response to store-overload-induce Ca2+ release (also indicated by a diagonal arrow in the I rel channel at the bottom). DAD = delayed after-depolarizations; Irel = Ca2+ release channel of the sarcoplasmic reticulum (RyR2). Inaca and Insca = currents of the Na/Ca exchanger and the Ca2+ sensitive nonspecific cation channel, respectively. Modified from Figure 4 of Am J Physiol Heart Circ Physiol 2010;298:H33-44 with permission. Ca2+ cycling revealed that SR Ca2+ ATPase (IUP) played an essential role in BAS-induced facilitation of DADmediated triggered activity (Figure 2) and, in addition to I Ca,L , it was essential for the facilitation of arrhythmogenesis under the influence of BAS. Thus, G406R Cav1.2 channel mutation confers not only a trigger but also a substrate for the development of ventricular arrhythmias which can be exaggerated by BAS. We concluded that, besides beta-adrenergic blockers and ICa,L channel blockers, an agent aimed at reduction of IUP may additionally provide antiarrhythmic efficacy in patients with TS (Figure 3). Similarly, we are currently applying this modeling method for other inherited arrhythmogenic disorders with adrenergically mediated ventricular arrhythmias such as Andersen-Tawil syndrome (LQT7) 7 and catecholaminergic polymorphic ventricular tachycardia. Preliminary results suggest that, depending on the underlying mechanism, the effective targeted site of antiarrhythmic therapy beyond beta-adrenergic receptors varies somewhat among these different forms of inherited arrhythmogenic disorders. We anticipate that the technique of computational modeling will be an integral part of translational research, providing direction for basic and clinical investigations. However, further refinement of the modeling methodology is required so as to enhance its predictive power.8 Acta Cardiol Sin 2010;26:139-41 Figure 3. Reduction of IUP suppress the inducibility of DAD-mediated triggered activity in the 23% G406R Cav1.2 mutant. Under the influence, pacing for 12 stimuli (the last indicated by a vertical arrow) readily provokes an onset of DAD-mediated triggered activity (top panel). Note reduction of IUP by 20% prevents induction of the arrhythmia (lower panel). IUP = Ca2+ uptake channel (SERCA) of the sarcoplasmic reticulum. Modified from Figure 7 of Am J Physiol Heart Circ Physiol 2010;298:H33-44 with permission. 140 Medical Modeling and Drug Discovery REFERENCES 24:65-74. 5. Sung RJ, Wu YH, Lai NH, et al. Beta-adrenergic modulation of arrhythmogenesis and identification of targeted sites of antiarrhythmic therapy in Timothy (LQT8) syndrome: a theoretical study. Am J Physiol Heart Circ Physiol 2010;298:H33-44. 6. Chan YS, Wu CT, Yeh YH, Kuo CT. Reappraisal of Luo-Rudy dynamic cell model. Acta Cardiol Sin 2010;26:69-80. 7. Sung RJ, Wu SN, Wu JS, et al. Electrophysiological mechanisms of ventricular arrhythmias in relation to Andersen-Tawil (LQT7) syndrome under conditions of reduced IK1: a simulation study. Am J Physiol Heart Circ Physiol 2006;291:H2597-605. 8. Best JM, Kamp TJ. A sympathetic model of L-type Ca2+ channel-triggered arrhythmias. Am J Physiol Heart Circ Physiol 2010;298:H3-4. 1. Luo CH, Rudy Y. A dynamic model of the cardiac ventricular action potential. II. Afterdepolarizations, triggered activity, and potentiation. Circ Res 1994;74:1097-113. 2. Faber GM, Silva J, Livshitz L, Rudy Y. Kinetic properties of the cardiac L-type Ca2+ channel and its role in myocyte electrophysiology: a theoretical investigation. Biophys J 2007;92:152243. 3. Faber GM, Rudy Y. Calsequestrin mutation and catecholaminergic polymorphic ventricular tachycardia: a simulation study of cellular mechanism. Cardiovasc Res 2007;75:79-88. 4. Sung RJ, Kuo CT, Wu SN, et al. Sudden cardiac death syndrome: age, gender, ethnicity, and genetics. Acta Cardiol Sin 2008; 141 Acta Cardiol Sin 2010;26:139-41